Inhibition of HIV-1 replication by a Tat RNA-binding domain peptide analog.
The peptidic compound, N-acetyl-Arg-Lys-Lys-Arg-Arg-Gln-Arg-Arg-Arg-Cys(biotin)-NH2 (Tat10-biotin), contains the 9-amino acid sequence from the basic domain of the Tat protein responsible for specific interaction with TAR RNA. The cysteine residue provides an attachment site for biotin, which acts as a cellular uptake enhancer. Tat10-biotin binds a fragment of TAR RNA (deltaTAR) avidly and specifically, as measured in an electrophoretic gel shift assay. Tat10-biotin inhibited tat gene-induced expression of a stably transfected chloramphenicol acetyl transferase (CAT) reporter gene linked to the HIV-1 long terminal repeat (LTR) in a model cell assay, but did not inhibit phorbol ester-induced expression of CAT, thereby demonstrating a Tat-dependent mechanism of inhibition. Inhibition of HIV-1 replication after acute infection of MT2 cells was demonstrated by absence of HIV-induced syncytium formation and cytotoxicity, as well as by suppression of reverse transcriptase production. These results suggest that a peptide or peptide mimetic capable of competing with the TAR RNA-binding domain of Tat protein might be useful as a therapeutic agent for AIDS.
Choudhury
I
I
Department of Molecular Genetics and Microbiology, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, Piscataway 08854-5635, USA.
Wang
J
J
Rabson
A B
AB
Stein
S
S
Pooyan
S
S
Stein
S
S
Leibowitz
M J
MJ
D019380:Anti-HIV Agents / Q000494:pharmacology*; D001692:Biological Transport; D001710:Biotin / Q000031:analogs & derivatives* / Q000494:pharmacology; D015500:Chloramphenicol O-Acetyltransferase / Q000096:biosynthesis; D016325:HIV Long Terminal Repeat; D015497:HIV-1 / Q000187:drug effects* / Q000254:growth & development; D009842:Oligopeptides / Q000494:pharmacology*; D010446:Peptide Fragments / Q000494:pharmacology; D011485:Protein Binding; D012367:RNA, Viral / Q000187:drug effects*; D016601:RNA-Binding Proteins / Q000494:pharmacology*; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D015533:Transcriptional Activation / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects
D019380:Anti-HIV Agents; D009842:Oligopeptides; D010446:Peptide Fragments; D012367:RNA, Viral; D016601:RNA-Binding Proteins; D011993:Recombinant Fusion Proteins; C110692:Tat10-biotin; D001710:Biotin; D015500:Chloramphenicol O-Acetyltransferase